Secretoneurin, a novel neuropeptide, is a potent chemoattractant for human eosinophils.
Secretoneurin (SN), a 33-amino acid neuropeptide, is derived from secretogranin II that is released from sensory afferent C-fibers by capsaicin. Described functions of secretoneurin include chemotaxis of monocytes and endothelial cells, and inhibition of endothelial cell proliferation. Inhibition of monocyte chemotaxis by staurosporine indicated involvement of specific signaling pathways. We have tested effects of SN, substance P (SP), and interleukin-8 (IL-8) on eosinophil migration in modified Boyden chambers including signaling mechanisms of neuropeptide and cytokine stimulation of human eosinophils. Experiments showed SN as eosinophil chemoattractant comparable in its potency to IL-8. Checkerboard analysis, usage of a specific anti-SN-antibody, and receptor desensitization experiments confirmed the chemotactic activity. Preincubation of the cells with effective concentrations of staurosporine or tyrphostin-23 showed no effect, whereas treatment with wortmannin (WTN) or 3-isobutyl-1-methylxantin (IBMX) completely blocked SN-induced migration. Additionally, experiments ruled out tyrphostin-23- and WTN-sensitive signaling pathways for SP-induced chemotaxis of eosinophils. We conclude that SN-stimulated human eosinophil chemotaxis is mediated via a unique and specific signal transduction pathway that involves activation of phosphodiesterases and WTN-sensitive enzymes, ie, phospholipase D and phosphatidylinositol-3-kinase. In contrast, we report that activation of the latter and tyrosine kinases is required for SP-induced chemotaxis of eosinophils.
Dunzendorfer
S
S
Laboratory of Intensive Care Medicine, the Division of General Internal Medicine, the Department of Medicine, University of Innsbruck, Innsbruck, Austria.
Schratzberger
P
P
Reinisch
N
N
Kähler
C M
CM
Wiedermann
C J
CJ
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D002396:Catechols / Q000494:pharmacology; D002630:Chemotactic Factors; D002633:Chemotaxis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004804:Eosinophils / Q000502:physiology*; D006801:Humans; D016209:Interleukin-8 / Q000494:pharmacology; D009479:Neuropeptides / Q000494:pharmacology / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010739:Phospholipase D / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D053381:Secretogranin II; D015398:Signal Transduction; D013373:Substance P / Q000494:pharmacology; D020032:Tyrphostins; D000077191:Wortmannin
D000730:Androstadienes; D002396:Catechols; D002630:Chemotactic Factors; D004791:Enzyme Inhibitors; D016209:Interleukin-8; D009479:Neuropeptides; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D053381:Secretogranin II; D020032:Tyrphostins; C081159:secretoneurin; D013373:Substance P; D011505:Protein-Tyrosine Kinases; D010739:Phospholipase D; C060641:tyrphostin A23; D015056:1-Methyl-3-isobutylxanthine; D000077191:Wortmannin